Orally administerable calcium supplement for cattle

ABSTRACT

A calcium ion containing composition comprising a water in oil emulsion having a dispersed aqueous phase and a continuous oil phase, which composition is orally administerable and palatable to cows without causing lesions of the stomach and which composition is effective in preventing milk fever, said composition further comprising a calcium salt which is dissolved in the aqueous phase to form a calcium ion containing aqueous phase solution, the calcium in the composition, calculated as free calcium ion, comprising 10 to 20 percent by weight of the composition, said composition further including from 0.5 to 10 percent oil soluble non-ionic emulsifier. The invention also includes the method of orally administering the composition to cows to treat milk fever.

The present invention concerns an orally administerable composition forprevention and treatment of calcium deficiency in cattle, e.g. milkfever, said composition containing as active component a readilyabsorbable calcium compound.

Milk fever is a disease which is particularly caused by a strong declinein the Ca content of the blood in the period immediately up to calvingand at the beginning of lactation. The predominant part (about 75%) ofthe incidences occur during the first 24 hours after calving (M.Dantzer, Dansk Vet. Tidsskr. 1987, 70, 4 15/2, p. 148-154). The diseaseis normally treated by intravenous injection of calcium, in particularin the form of calcium borongluconate.

In Denmark 4-6% of first-time parturitions are complicated by milkfever, but in Sweden the figure is even higher, about 8%, cf. G.Jonsson, The Veterinary Record, (1978), 102, 165-169. However, there areconsiderably variations between the herds, depending upon race, yield,average age and feed composition.

Cows which have once suffered from milk fever are particularlypredisposed to acquire the disease again at the time of subsequentparturitions, and the disease occurs frequently in older cows (Dantzer,op. cit.).

A preferred method, cf. G. Jonsson op. cit., to prevent milk fever isshort term oral administration of readily absorbed calcium salts. Therapid absorption of calcium from a calcium chloride solution has beendemonstrated by i.a. Hallgren, Wien. Tierartztl. Mschr. 52 (1965), p.359-369, whose preliminary experiments showed a good preventive effect.However, the bitter taste and locally irritating effect of calciumchloride entail that the cows are extremely unwilling to take thesolutions, which involves a risk of aspiration and consequent aspirationpneumonia, etching of lung and dead. A stomach probe was therefore usedin Hallgren's experiments so that the solution was administered directlyin the stomach.

It goes without saying that this method is not feasible as a generalprevention without veterinary assistance.

To remedy these drawbacks, CaCl₂ in the form of viscous liquids havebeen used for several years. Since cows cannot spit, they generally haveno alternative but to swallow liquids which are so viscous that they donot run out of the mouth.

A commercially available product contains CaCl₂ and MgO in a viscoussolution. This product is not taken willingly by the cows and thereforeinvolves a risk of aspiration.

The aspiration problem can be reduced additionally by mixing calciumchloride in gels on the basis of water and inert cellulose derivatives,such as hydroxyethylcellulose or ethylcellulose. The U.S. Pat. No.3,461,203 reports experiments where water-free CaCl₂ in amounts of 232,115 and 100 were mixed with 9-10 g of hydroxyethylcellulose and water upto 450-400 ml. These gels were administered daily for 5-10 days, ofwhich two days were post partum. The milk fever incidence was reduced byfrom about 50% in the control groups to about 10% in the treated groups.According to G. Jonsson, op. cit., the drawbacks of this method are thedifficulty in predicting calving with sufficient accuracy, just as thefarmers regard the method as very laborious, in particular because ofthe resistance of the cows.

In view of this Jonsson and associates shortened the gel treatment, butstill administered 150 g or 100 g of water-free CaCl₂ dispersed inhydroxy ethyl cellulose and water up to 450 ml leading to a reduction ofthe milk fever incidence from 46 to 23%.

However, Jonsson concluded that even though gel intake is relativelyconvenient, voluntary intake of CaCl₂ would be better. Jonsson thereforedisguised the bitter taste of CaCl₂ in a feed supplement, but obtainedno preventive effect on milk fever, which he attributes to the fact thatalmost all cows cease eating on the day of calving or the day before.

Dantzer, op. cit., moreover states that CaCl₂ gels are acid and takenonly unwillingly by the cows.

As mentioned more fully below, Jess Jorgensen et al., Dansk Vet.Tidsskr. 1990, 73, 31/2, p. 140 reports examinations which show thatCaCl₂ gels on the basis of hydroxyethylcellulose can have an etchingeffect on the stomach wall in cows.

Dantzer also examined the effect of the so-called calving lime whichconsists of 95% CaHPO₄ and 5% MgO as well as 96000 vitamin D₃ per dose.

Dantzer reports that the product is willingly taken perorally by thecows. MgO is added because many cows suffer from hypomagnesemaemia,which makes them predisposed to milk fever. Dantzer's conclusion to theadmittedly limited test material is that calving lime is less effectivethan CaCl₂ gel. The reason is presumably the limited solubility ofCaHPO₄ and the consequent limited calcium absorption.

Thus, there is still a need for a calcium based composition whicheffectively prevents milk fever, which is taken willingly by the cows,and which is not vitiated by any risk of aspiration upon oral intake.

The invention is based on the surprising finding that the troubles canbe remedied by the use of calcium compounds, in particular calciumchloride, if the calcium compound is suspended or emulsified in an oilphase.

In view of this the invention concerns an orally administerablecomposition for prevention or treatment of milk fever in cattle, saidcomposition containing as active ingredient a readily absorbable calciumcompound, the composition being characterized in that the calciumcompound is suspended or emulsified in an oil phase.

As explained by Hallgren and Dantzer, op. cit., the total calciumcontent in serum consists of a diffusable portion (about 55%) inequilibrium with a protein bonded portion (about 45%). The diffusableportion, which is the readily useful portion, consists of about 45% freecalcium ions and about 10% complex bonded calcium. This equilibrium ispH dependent and is shifted towards free calcium ions with a decliningpH.

Since only the ionized calcium (Ca⁺⁺) is absorbed from the intestine ofthe cow, the constituent calcium compound must therefore be watersoluble, and to make the pH of the serum go in an acidic direction saltshaving an acidosing (acidotic) effect, such as calcium chloride, arepreferred.

Also other soluble calcium salts are useful, such as calcium formate,calcium acetate, calcium propionate, calcium gluconate, calciumborongluconate, calcium lactate, calcium laevulate, and calciumascorbate.

The oil phase is formed by an edible oil. Preferred oils are vegetableoils, such as soybean oil, repeseed oil, olive oil, groundnut oil,apricot kernel oil, grapeseed oil, almond oil, linseed oil, peach kerneloil, palm oil, coconut oil, castor oil, sunflower oil and corn oil. Alsoanimal oils, such as fish oils, can be used.

As mentioned, the composition of the invention is characterized in thatthe calcium compound is suspended or emulsified in an oil phase.

Based on weight, the composition may thus comprise 0-80%, in particular0-70% water phase, and 100-20%, in particular 100-30% oil phase. Thepreferred mixing ratio is 40-70% water phase and 60-30% oil phase.

The content of calcium calculated as free Ca⁺⁺ in the finished mixtureis 1-25% by weight, preferably 10-20%.

It could not be expected in advance that it would be possible toformulate emulsions with such a high content of dissolved calciumcompound in such a large amount of water phase, i.a. because of theincreased density and increased ion strength of the water phase.

In the preferred embodiment, the calcium compound is thus dissolved inthe aqueous phase in a water-in-oil emulsion. To ensure suitableemulsion stability, the emulsion contains one or more emulsifiers.Suitable emulsifiers are e.g. oil soluble non-ionic emulsifiers, inparticular esters of polyvalent alcohols, preferably glycerol, withfatty acids or polymerized oils.

It has been found that a particularly good emulsion stability may beobtained with polyglycerol esters of polymerized soybean oil.

The concrete emulsifier selection and emulsifier amount depend i.a. uponthe ratio of water phase to oil phase, the type of the oil phase and theamount of dissolved calcium compound.

The most expedient emulsifier and emulsifier amount can thus be found byexperiments.

The emulsifier is used in an amount of 0.5-10%, calculated on thefinished mixture, in particular 1-4%, preferably 1.5-2.5%.

The composition of the invention may moreover contain additives such asmineral supplements, e.g. magnesium or selenium, vitamin D andflavouring substances, sweetening agents, antioxidants andpreservatives. If desired, thickeners may moreover be added to one orboth phases.

To produce the present composition in the form of an emulsion, thecalcium compound is dissolved in water together with optionalpreservatives and thickeners and is heated to about 50° C. This solutionis mixed with an about 50° C. hot solution of emulsifier and optionalantioxidants, sweetening agents and flavouring substances in the oilused with vigorous stirring. The resulting emulsion may be homogenizedif desired.

The suspension may be produced analogously, however without addition ofwater.

The desirable peroral dose is 50 g of free Ca⁺⁺ which is administered inprophylactic treatment 24 hours before expected calving, immediatelyafter calving as well as 12 and 24 hours later.

Peroral treatment is also used as a supplement to intraveneous calciumtreatment and is then dosed with 50 g of Ca⁺⁺ 4, 12 and optionally 24hours after the intraveneous treatment.

A composition according to the invention may e.g. be composed asfollows:

    ______________________________________                                        CaCl.sub.2, Pharmacopea Nordica                                                                    25%                                                      Soybean oil          47%                                                      Emulsifier            3%                                                      Water                25%                                                      Flavouring substances                                                                              0.04%                                                    (coconut and vanilla)                                                         Saccharine sodium    0.01%                                                    Antioxidant                                                                   Preservative                                                                  ______________________________________                                    

A typical composition may consist of:

    ______________________________________                                        CaCl.sub.2, 6H.sub.2 O                                                                         300 g  (corresponding to                                                             50 g of Ca.sup.++                                     Water            100 g                                                        Emulsifier        16 g                                                        Soybean oil      380 g                                                        Additives         4 g                                                                          800 g                                                        ______________________________________                                    

The commercially available products "Calol®" and "KOVEL®" respectivelycontain

    ______________________________________                                        CaCl.sub.2, 2H.sub.2 O                                                                           200 g      200 g                                           Soybean oil        280 g      380 g                                           Water              200 g      200 g                                           Auxiliary substances                                                                              20 g       20 g                                           and flavour                                                                                      700 g      800 g                                           ______________________________________                                    

The composition of the invention is being tested in a large number ofherds.

Initial experiments have shown that the cows willingly take thecomposition. The composition has till now been tested as a supplementfor intravenous administration of calcium borongluconate in confirmedmilk fever incidences, where CaCl₂ gel as well as placebo control wereused for comparison. 8 g of Ca⁺⁺ were administered intraveneously, aswell as 8 g of Ca⁺⁺ subcutaneously for precipitation in three groups often cows, where two groups were subsequently treated with 50 g of Ca⁺⁺either as Calol®/KOVEL® or as CaCl₂ gel. The third group served ascontrol.

Both oral treatments showed significant effects on the clinicalsymptoms. In terms of effect, there was no difference betweenCalol®/KOVEL® and the gel, but Calol®/KOVEL® was accepted much better bythe cows and were much easier to administer. The test will be reportedat the XVI World Buiatrics Congress, Bahia, Brazil, Wermuth et al. "NewTreatment of Milkfever".

Jess Jorgensen et al., Dansk Vet. Tidsskrift, 1990, 73, 3 1/2, p. 140refers to comparitive examinations between CaCl₂ gels withhydroxyethylcellulose as gel former and a composition according to theinvention in the form of an emulsion in 380 g of soybean oil. Bothcompositions contained 400 ml, 49% aqueous CaCl₂, H₂ O.

It was concluded that the gel composition in the dose used can causepronounced clinical and pathological side effects, in particular by wayof lesions of the stomach wall while the composition of the inventiononly involved relatively mild clinical symptoms and superficial or nopathological lesions.

In a further examination by the National Institut of Animal Science, OleAaes "Report on the influence of various culture calcium compositions onfeed intake when feeding according to appetite" it was demonstratedthat, in addition to the above-mentioned lesions on the stomach wall,the CaCl₂ gels also reduced the appetite. Thus, feed intake measured askg dry matter was reduced by 2.8 feed units (FU), while Calol®/KOVEL®only reduced the feed intake by 2.1 FU. However, to this should be addedthat about 3.2 FU were added with the soybean oil, which will give anunchanged or positive energy balance even with a digestibility of about75%.

I claim:
 1. A method for treating milk fever in cows which comprisesorally administering to cows in need thereof an effective amount of acalcium ion containing composition comprising a water in oil emulsionhaving a dispersed aqueous phase and a continuous oil phase, whichcomposition is orally administerable and palatable to cows, saidcomposition further comprising calcium chloride which is dissolved inthe aqueous phase to form a calcium ion containing aqueous phasesolution, the calcium in the composition, calculated as free calciumion, comprising 10 to 20 percent by weight of the composition, saidcomposition further including from 0.5 to 10 percent emulsifier; whereinsaid composition is orally administered in a plurality of doses within24 hours before and 24 hours after calving to provide a total of atleast 150 g of free Ca⁺⁺ ion.
 2. The method of claim 1 wherein saidemulsion includes from 40 to 70 percent aqueous phase and 30 to 60percent oil phase.
 3. The method of claim 1 wherein the emulsifier is anester of a polyvalent alcohol with a fatty acid or of a polymerized oil.4. The method of claim 1 wherein the emulsifier is a polygycerol esterof polymerized soybean oil.
 5. The method of claim 1 wherein the oilphase consists of an edible oil selected from the group consisting ofsoybean oil, rapeseed oil, groundnut oil, and grapeseed oil.
 6. Themethod of claim 1 wherein the composition further contains additivesselected from the group consisting of magnesium salts, vitamin D,flavorings, sweeteners, antioxidants, and preservatives.